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Viruses. 2019 Jan 25;11(2). pii: E100. doi: 10.3390/v11020100.

HIV-1 Fusion with CD4+ T cells Is Promoted by Proteins Involved in Endocytosis and Intracellular Membrane Trafficking.

Author information

1
Department of Pediatric, Division of Infectious Diseases, Emory University School of Medicine, 2015 Uppergate Drive, Atlanta, GA 30322, USA. mmarin@emory.edu.
2
Functional Genomics Center, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA. yulia@lji.org.
3
Department of Pediatric, Division of Infectious Diseases, Emory University School of Medicine, 2015 Uppergate Drive, Atlanta, GA 30322, USA. cs.mason@outlook.com.
4
Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. schanda@sbpdiscovery.org.
5
Department of Pediatric, Division of Infectious Diseases, Emory University School of Medicine, 2015 Uppergate Drive, Atlanta, GA 30322, USA. gmeliki@emory.edu.
6
Children's Healthcare of Atlanta, Atlanta, GA 30322, USA. gmeliki@emory.edu.

Abstract

The HIV-1 entry pathway into permissive cells has been a subject of debate. Accumulating evidence, including our previous single virus tracking results, suggests that HIV-1 can enter different cell types via endocytosis and CD4/coreceptor-dependent fusion with endosomes. However, recent studies that employed indirect techniques to infer the sites of HIV-1 entry into CD4+ T cells have concluded that endocytosis does not contribute to infection. To assess whether HIV-1 enters these cells via endocytosis, we probed the role of intracellular trafficking in HIV-1 entry/fusion by a targeted shRNA screen in a CD4+ T cell line. We performed a screen utilizing a direct virus-cell fusion assay as readout and identified several host proteins involved in endosomal trafficking/maturation, including Rab5A and sorting nexins, as factors regulating HIV-1 fusion and infection. Knockdown of these proteins inhibited HIV-1 fusion irrespective of coreceptor tropism, without altering the CD4 or coreceptor expression, or compromising the virus' ability to mediate fusion of two adjacent cells initiated by virus-plasma membrane fusion. Ectopic expression of Rab5A in non-permissive cells harboring Rab5A shRNAs partially restored the HIV-cell fusion. Together, these results implicate endocytic machinery in productive HIV-1 entry into CD4+ T cells.

KEYWORDS:

HIV; cell fusion; endocytosis; membrane trafficking; shRNA screen; virus fusion

PMID:
30691001
DOI:
10.3390/v11020100
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